Reproductive and endocrine gonadal functions in adults following multidrug chemotherapy for acute lymphoblastic or undifferentiated leukemia.

The impact of aggressive chemotherapy on reproductive and endocrine gonadal function was studied in ten women and ten men with acute lymphoblastic leukemia (ALL) or acute undifferentiated leukemia (AUL) in complete remission. Hormone determinations, sperm analyses, measurements of basal body temperature, and interviews with a standardized questionnaire were used for diagnostic evaluation. Elevated serum follicle-stimulating hormone (FSH) levels and azoospermia were seen in all male patients after completion of induction and consolidation therapy as a result of germ cell and stem cell loss. Recovery of spermatogenesis, as indicated by normalization of serum FSH values and sperm density, occurred in the second year of maintenance therapy in all men. Serum testosterone and luteinizing hormone (LH) values remained within normal limits indicating resistance of Leydig cells to chemotherapy. All female patients showed normal serum levels of gonadal steroids and gonadotropins, as well as an adequate increase in basal body temperature after intensified chemotherapy, indicating intact follicle function and ovulation. Most patients reported normal sexual functions after induction and consolidation therapy. These results demonstrate that multidrug chemotherapy induced significant impairment of reproductive function in all male patients with early and complete recovery. In contrast, endocrine gonadal function was unaffected in men treated with ALL/AUL. In female patients, neither reproductive nor endocrine functions were influenced by aggressive chemotherapy.

Regulation of FSH secretion: use of hydroxyurea to deplete germinal epithelium.

Hydroxyurea, a chemotherapeutic agent that prevents mitosis by inhibiting DNA synthesis, was administered to adult male rats for 70 days. Plasma FSH and LH showed no systematic trend although severe germinal cell depletion was produced. These data suggest that the cell(s) of the seminiferous tubule involved in FSH regulation must be either the type A spermatogonium or the Sertoli cell.

Developmental changes in testicular gonadotropin receptors: plasma gonadotropins and plasma testosterone in the rat.

The relationships between plasma gonadotropins, testicular gonadotropin receptors, and plasma testosterone were examined during neonatal life and throughout sexual maturation in the rat. The binding affinity of testicular LH receptors (2.4 X 10(10) M-1) was significantly higher than that of FSH receptors (2.1 X 10(9) M-1) at all stages of development. The concentration of FSH receptors in the testis reached a peak between 10-15 days of age, then fell to a constant level from 25-90 days. However, the testis content of FSH receptors increased continually with age and reached a plateau at day 60. Plasma FSH declined after birth to a nadir at 15 days, then rose rapidly to a peak at day 38, and fell to a plateau from day 50 through adult life. In contrast to the rapidly changing profile of plasma FSH during early maturation, alterations in plasma LH were less marked throughout development. Although a progressive rise in plasma LH concentration was observed between days 36-51, the simultaneous changes in testicular LH receptors and plasma testosterone were much more prominent. Testicular LH receptors showed a continuous increase in concentration and total number with advancing age and testis growth. The major rise in LH receptor concentration occurred between 15-38 days age, at the same time as the rise in plasma FSH concentration and the phase of rapid testicular growth. Plasma testosterone fell during the 8th-24th days after birth, then rose rapidly between days 35-55. The pubertal rise in plasma testosterone occurred about 15 days after testicular LH receptors began to increase and was coincident with the continuing rise in LH receptor content from day 35 until day 55 and with the progressive increase in plasma LH during this period. These observations have demonstrated that the early development of testicular FSH receptors in followed by a prominent rise in plasma FSH, with concomitant increases in testicular growth and LH receptor concentration. The resulting increase in gonadal sensitivity to LH could be responsible for the marked increase in secretion of testosterone which occurs during puberty in the presence of a relatively small change in the circulating LH concentration. The sequence of changes observed in gonadotropins and their testicular receptors is consistent with the view that FSH-induced testicular sensitivity to LH is an important factor in sexual maturation in the male rat.

Reproductive and endocrine gonadal capacity in patients treated with COPP chemotherapy for Hodgkin's disease.

Testicular and ovarian functions were assessed in 33 patients with Hodgkin's disease 1 to 17 years after cessation of COPP chemotherapy with cyclophosphamide, vincristine, procarbazine, prednisone. Diagnostic procedures consisted of hormone measurements, interviews, and semen analyses. In women serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17 beta-estradiol, progesterone, prolactin, and in men FSH, LH, 17 beta-estradiol, testosterone, and prolactin were determined. Semen analyses were performed in all men. Information concerning pregnancies, pregnancy outcome, future fertility wishes, sexual functions, menstrual pattern, and incidence of premature menopausal symptoms was ascertained by interview and questionnaire. Nineteen of 19 (100%) men showed elevated serum FSH levels between 715 and 1910 (median 1095) ng/ml and azoospermia, 1 to 11 years after therapy. Serum levels of testosterone were within normal limits in 18/19 (95%) of the men, and LH values were normal in all men. Permanent ovarian failure occurred in 8/14 (57%) women, causing infertility and premature menopausal symptoms. The incidence of ovarian failure in women over 24 years was 86% (6/7) versus 28% (2/7) in those under 24 years at the time of treatment. In women receiving estrogen replacement, incidence and severity of these symptoms were significantly reduced. Of 14 women 3 (21%) became pregnant and delivered 5 healthy children after treatment. Our results suggest irreversible sterility and normal Leydig cell function after COPP chemotherapy in all men. Drug-induced ovarian failure was age-related and caused premature menopausal symptoms, detracting from the quality of the patient's life. To reduce premature menopausal symptoms and to prevent adverse cardiovascular and metabolic late sequelae, hormonal replacement is indicated. Pregnancies ending in normal live births can be achieved after COPP chemotherapy in young women. In both men and women, serum FSH and LH levels proved to be feasible markers to determine degree and duration of endocrine and reproductive gonadal injury after chemotherapy.

Hereditary bimanual synkinesis combined with hypogonadotropic hypogonadism and anosmia in four brothers.

A new genetic syndrome of the combined occurrence of hypogonadotropic hypogonadism, anosmia (Kallmann syndrome) and congenital mirror movements in four brothers is presented. Mirror movements were manifest only within the distal parts of the upper extremities and resembled congenital mirror movements described for isolated or familial cases or those occurring in combination with other genetic defects. The hypothesis is supported, that a midline fusion disorder with preponderance of uncrossed pyramidal tract fibers is a major pathogenetic factor for the occurrence of congenital mirror movements.

[Feasibility and relevance of tumor volumetry for stage classification and assessment of remission of germ cell tumors]. / Praktikabilität und Relevanz der Tumorvolumetrie zur Stadienklassifikation und Remissionsbeurteilung bei Keimzelltumoren.

Although tumor load has proven to be the most relevant prognostic factor in disseminated germ cell tumors (GCT), methods to determine tumor volume for staging have not been studied so far. In a prospective study, we therefore measured the volume of metastases before and during chemotherapy in 27 patients with disseminated GCT. Abdominal tumor volume was calculated using a General Electric CT scan 8800. Total volume was determined by cumulation of 1 cm slices measured by a cursor. Pulmonary volume was calculated by taking each metastasis as a sphere using V = 0.523 x d3, where V = volume and d = diameter. We used linear regression analysis to determine the dependence of tumor markers on volume. Before chemotherapy, the median tumor volume of all patients was 237 (range 4-2690) cm3. The tumor volume was 1-100 cm3 in 30%, 101-500 cm3 in 41%, and over 500 cm3 in 29% of the patients. NED (no evidence of disease) was achieved in 8/8 patients presenting with a small (1-100 cm3) and 9/10 with a moderate (101-500 cm3) tumor volume. In contrast, only 1/8 with advanced tumor load (greater than 500 cm3) achieved NED. While there was a significant correlation between the initial and the residual tumor volume (P = 0.0024, r = 0.72), there was none between the tumor volume and alpha fetoprotein, beta human chorionic gonadotropin, and lactate dehydrogenase. These results suggest that radiological determination of tumor volume is a reproducible and accurate staging method.

[Clinical examination and endocrinologic diagnosis of male infertility (author's transl)]. / Klinische Untersuchung und endokrinologische Diagnostik bei infertilen Männern.

The importance of history and the findings of clinical examination is often underestimated in examination for male fertility. From the data so obtained arises the indication for examining the exocrine (spermiogram) and endocrine function of the hypothalamo-hypophysealgonad axis (testosterone, LH, FSH, prolactin, GRH and HCG stimulation tests). The numerous causes of fertility impairment outside the endocrinological field (internal medical and urological diseases, consumption behavior, psychic disturbances, medicines etc) are referred to. The couple seeking help are spared unnecessary deviations through good cooperation between the gynecologist and andrologically oriented disciplines.

Diurnal variation of cytosol estrogen receptors in the liver from adult male rats.

The adult male rats showed a diurnal variation for estrogen receptors in liver with the zenith at 08.00 h and the nadir at 12.00 h. Estradiol-17 beta showed the zenith at 04.00 h and the nadir at noon. Testosterone had the zenith at 16.00 h and the nadir at 20.00 h. Prolactin showed a circadian variation with higher levels during the light period. It is concluded, that there is a diurnal variation for the cytosolic estrogen receptors in the liver from adult male rats.

[Tiapride therapy of centrally produced dyskinesia. Examination of the serum levels of protein, LH and FSH (author's transl)]. / Zur Therapie zentralbedingter Bewegungsanomalien mit Tiaprid. Untersuchung des Serumspiegels von Prolactin, LH and FSH.

The effect of N-(2-diethylaminoethyl)-2-methoxy-5-(methylsulfonyl)-benzamide hydrochloride (tiapride, Tiapridex), a dopamine antagonist, on the serum levels of prolactin, luteinising hormone (LH) and follicle-stimulating hormone (FSH) was studied on 20 healthy individuals and 10 patients with dyskinesia resulting from extrapyramidal disorders. Daily doses of 300 mg in healthy subjects and 300-800 mg in patients with dyskinesia resulted from CNS disorders, were found to increase serum prolactin levels without causing amenorrhoea or galactorrhoea. The drug seemed to have no effect on LH and FSH concentrations in the serum.

Further evidence that prolactin does not affect gonadotropin release at pituitary level.

In a primary monolayer cell culture of the anterior pituitary from mature male rats the effects of exogenous rPrl (rPrl exog.) and endogenously secreted rPrl (rPrl endog.) on basal and LHRH stimulated LH secretion were investigated. In pilot studies basal Prl- and LH secretion as well as influence of various LHRH concentrations (10(-1)-10(+3) ng/ml) on Prl- and LH release were observed. The influence of exogenous rPrl was studied at various concentrations (50-500 ng/ml) and with preincubation periods of 2 hrs and 6 hrs before starting LHRH stimulation. The dopamine agonist bromocriptine and the dopamine antagonist sulpirid were preferentially used to prove physiologic function of the cell system presented. Basal LH secretion started after a delay of 3 hrs, whereas basal Prl secretion began immediately showing a linear rise for 9 hrs. LHRH stimulation resulted in a non-linear dose and time dependent LH secretion. LHRH showed no influence on endogenous Prl (rPrl endog.) secretion of the mammotroph cells. Exogenous Prl (rPrl exog.) did not affect spontaneous Prl release excluding ultra short loop inhibition in this cell system. Furthermore, exogenous Prl had no effect on either basal or LHRH stimulated LH secretion even after a preincubation period of up to 6 hrs and at concentrations generally observed for prolactin secreting tumors. Bromocriptine suppressed endogenous Prl release and did not affect LH secretion. Sulpirid had no influence on either Prl or LH secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Reproductive toxicity with and without LHRHA administration during adjuvant chemotherapy in patients with germ cell tumors.

In order to evaluate the protective efficacy of an agonist of luteinizing hormone releasing hormone (LHRHA) on spermatogenic stem cells, we undertook a prospective study in patients with germ cell tumors. Following orchiectomy and unilateral lymph node dissection all patients received adjuvant chemotherapy consisting of 2 courses of PVB regimen (cisplatin, vinblastine and bleomycin). Six men were treated with LHRHA (d-Ser-(TBU)6 LHRH ethylamide) before, during and after PVB chemotherapy. Eight patients without LHRHA protection served as controls, receiving the identical chemotherapy. Follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone were within normal limits before therapy in all patients. In 6/6 protected patients, serum levels of FSH, LH and testosterone were effectively suppressed during pre-chemotherapeutic LHRHA administration. All protected patients showed elevated serum FSH levels and azoospermia after cessation of chemotherapy and LHRHA treatment due to germ and stem cell loss. Median FSH level and sperm density of the protected group normalized within 24 months after chemotherapy. In all unprotected patients elevated FSH values and azoospermia also occurred after chemotherapy. Likewise, median FSH level and sperm density normalized spontaneously in this group within 24 months after chemotherapy. Our results suggest completely reversible reproductive toxicity two years after 2 courses of adjuvant chemotherapy in all patients. Administration of LHRHA during chemotherapy seems to have no protective effects on germ cells since both groups developed reproductive toxicity. Furthermore, recovery time was identical in the protected and unprotected patients. FSH and LH could be used as diagnostic markers to assess the degree and duration of reproductive and endocrine gonadal toxicity after chemotherapy.

[Global pituitary stimulation test with releasing hormones]. / Globaler Hypophysenstimulationstest mit Releasing-Hormonen.

The endocrine function of the thyroid and gonads has for long been investigated using the corresponding releasing hormones (TRH- and LHRH-test, respectively). The adrenal cortex has, up to now, been stimulated using insulin-induced hypoglycaemia or lysine-vasopressin and growth hormone stimulated using arginine. New diagnostic possibilities have arisen with the isolation of the corresponding releasing-hormones, CRF and GRF, and with the availability of these too for clinical use. Using the four above mentioned releasing-hormones in a global pituitary-stimulation-test, the secretion of ACTH, cortisol, STH, TSH, LH, FSH and prolactin hormones can now be examined together.

Combined pituitary stimulation test: interactions of hypothalamic releasing hormones in man.

The use of hypothalamic releasing hormones for the clinical assessment of anterior pituitary function is both simple and free of severe side effects. Tests with the recently discovered substances GRF and CRF as well as with combinations of several releasing hormones are therefore used in many clinics. A reliable interpretation of such combined tests, however, is only possible when positive or negative interactions between these releasing hormones are known. After a rest of 2 h to reach basal cortisol levels, 7 groups of 5 male volunteers each received an iv bolus injection consisting of either: A): GRF (100 micrograms) + CRF (50 micrograms) + TRH (200 micrograms) + LHRH (100 micrograms), B): CRF + TRH, C): GRF + TRH, D): LHRH + TRH, E): TRH, F): GRF, G): CRF. During the following 2 h, GH, TSH, cortisol, LH, FSH and prolactin were measured every 15 min. The TSH response after the injection of all 4 releasing hormones was significantly higher (delta TSH = 16.5 +/- 2.0 microU/ml, x +/- SE) compared to the injection of TRH alone (delta TSH = 9.3 +/- 1.4 microU/ml; p less than 0.025). This increment in TSH secretion was confirmed when 2 groups of 5 female volunteers were studied with the TRH-test (delta TSH = 9.9 +/- 1.8 microU/ml) or the combination of all four releasing hormones (delta TSH = 16.8 +/- 2.9 microU/ml; p less than 0.05). This exaggerated TSH-response to TRH was demonstrated to be entirely due to simultaneous administration of GRF, whereas CRF and LHRH in combination with TRH had no additional effect on TSH release.(ABSTRACT TRUNCATED AT 250 WORDS)

Normalisation of gonadotropin release by pump assisted pulsatile gonadotropin releasing hormone (GnRH) replacement in hypogonadotropic men.

Pulsatile GnRH therapy is indicated for men with inborn hypothalamic hypogonadotropic hypogonadism and those with acquired gonadotropin deficiency due to hypothalamic disfunction. Oligospermia with hypothalamic GnRH deficiency is a rare indication for efficient GnRH therapy. Based on extended own experience and on the experience of numerous other groups, pulsatile GnRH therapy should be administered as follows: Onset of therapy should not start before the 16th year of age with clearly diagnosed delayed pubertal development. Subcutaneous administration of GnRH is preferred. The cannula should be changed every other day. Injection solutions should not contain Heparin. For diagnostic use or for inefficient subcutaneous therapy, continuation of intravenous therapy containing Heparin in the solution is recommended. The dosage should be measured on the increase of testosterone with stepwise increase of GnRH (25-200 ng/kg/pulse; 2.5-20 micrograms/pulse). As a pulse interval, 120 minutes appeared to be the most efficient, however 90 minutes of pulse intervals may also be efficient. The duration of therapy should be at least three months controlled on the testosterone level, the testes' volume and later on the sperm count.

Chronic gonadal toxicity in patients with testicular cancer after chemotherapy.

Forty-five patients with disseminated testicular cancer treated with cisplatin, vinblastine and bleomycin +/- adriamycin (PVB +/- A) were studied to establish the impact of chemotherapy on hormonal and reproductive functions. Data on FSH, LH, testosterone, prolactin, semen analyses and sexual functions were obtained before, during and 1-6 yr after chemotherapy. Mean LH, testosterone and prolactin levels were within normal limits before, during and after chemotherapy. Twenty per cent (4/20) of the patients revealed pathologically elevated FSH levels due to pretreatment gonadal dysfunction. Germinal aplasia occurred in all patients in the first year after chemotherapy, as 100% rendered azoospermic and 95% showed statistically significant elevated FSH values (P = 0.001). In the third year after chemotherapy 80% (8/10) of the patients showed normalization of FSH levels and 100% (7/7) recovery of sperm production but with a high degree of immotile sperms. Although these results emphasize the restitution of spermatogenesis in the third year after cessation of PVB-regimen, the minority of these patients fathered children, probably due to reduced sperm motility.

Adrenal insufficiency secondary to hypothalamic corticotropin releasing factor (CRF) insufficiency with hyperpigmentation: a case report.

Partial adrenocortical insufficiency as a result of an insufficiency of the hypothalamic corticotropin releasing factor (CRF) was demonstrated in a 53-year-old female patient. Somatotropic, gonadotropic and thyreotropic functions of the pituitary gland were shown to be normal by a simultaneous pituitary stimulation test. This held true especially for the adrenocorticotrophic function: administration of lysine-vasopressin induced a normal rise in immunoreactive plasma-ACTH. Thus, a pituitary defect as a primary cause of the disease could be excluded and evidence was provided that there was a lack in hypothalamic stimulae absence of elevated ACTH levels hyperpigmentation of the skin existed. Possible explanations are discussed.

Metabolic and hormonal reactions during training in junior oarsmen.

This study evaluated strain reactions in young athletes (mean age: 17.6 years). Of 35 male rowers, 21 were selected by rowing ergometer tests to take part in a 26-day training camp before the World Championships in 1989. Blood samples were obtained in the morning of the day after rowing ergometer tests and on the 16th and 26th day. Cortisol (C), testosterone (T), sexual-hormone-binding globulin (SHBG), urea and creatine kinase (CK) were determined in serum and free testosterone (FT) was calculated. In the nonselected rowers C was 10% higher, FT 20% lower, and CK 42% higher compared to the selected rowers. During training, C was related to the intensity of training. It remained constant in phase 1 (12 days, increased volume of training) and increased in phase 2 (10 days, decreased volume and higher intensity). FT decreased in phase 1 and increased in phase 2. Urea showed a close relationship to training volume. CK levels decreased during the training volume. CK levels decreased during the training period as an adaptation to the training. Despite a high training load, there were no indications of overstrain reactions in these young athletes.

Stress hormone response during and after cardiopulmonary resuscitation.

The purpose of this study was to assess whether plasma adrenocorticotropin, cortisol, vasopressin, and renin concentrations are higher in resuscitated than in nonresuscitated patients during cardiopulmonary resuscitation, and whether there are possible correlations between these hormones and blood pressure or heart rate in the immediate postresuscitation phase. Of 34 consecutive patients (36-85 yr of age) with out-of-hospital cardiac arrest, 20 could be successfully resuscitated and admitted to hospital, whereas in the remaining 14 patients restoration of spontaneous circulation could not be achieved. During cardiopulmonary resuscitation, median adrenocorticotropin, cortisol, vasopressin, and renin concentrations in the external jugular vein were 237 pg/ml, 32.6 micrograms/dl, 122 pg/ml, and 46.5 ng/l, respectively, in resuscitated patients, and 45 pg/ml (P = 0.018), 18.4 micrograms/dl (P = 0.481), 88 pg/ml (P = 0.049), and 11 ng/l (P = 0.017), respectively, in nonresuscitated patients. Median adrenocorticotropin, cortisol, vasopressin, and renin concentrations were 101 pg/ml, 34.6 micrograms/dl, 22 pg/ml, and 25 ng/l, respectively, 60 min after successful resuscitation. No significant correlations were found between hormone levels and blood pressure or heart rate, but there was a significant negative correlation between the interval from collapse to the start of cardiopulmonary resuscitation and plasma cortisol concentrations during cardiopulmonary resuscitation (Spearman rank correlation coefficient = -0.967, P less than 0.001), indicating an impaired cortisol release from the adrenal cortex. The lower hormone concentrations of the nonresuscitated patients measured during cardiopulmonary resuscitation might indicate an impairment in neuroendocrine response.